Regular AA-BB-type bio-analogous poly(ester amides) (PEAs), consisting of nontoxic building blocks, such as hydrophobic α-amino acids, aliphatic diols and di-carboxylic acids have been proven to be important materials for biomedical applications because of their excellent blood and tissue compatibility (K. DeFife et al. Transcatheter Cardiovascular Therapeutics—TCT 2004 Conference. Poster presentation. Washington D.C. 2004) and biologic degradation profiles (G. Tsitlanadze, et al. J. Biomater. Sci. Polymer Edn. (2004). 15:1-24). Controlled enzymatic degradation and low nonspecific degradation rates of PEAs make them attractive for drug delivery applications.
These properties of PEAs provide advantages over widely used aliphatic polyesters, such as polylactic acid (PLA) and polyglycolic acid (PGA). Aliphatic ester-groups in macromolecules of PLA and PGA contribute to rapid hydrolytic degradation rates, but polymer surfaces are known to display poor adhesion and cell growth, which properties are important indicators of cell-biomaterial interactions (Cook, A D, et al. J. Biomed. Mater. Res., (1997). 35: 513-523).
Due to increased environmental concerns, other aliphatic biodegradable polyesters have also gained renewed interest as an alternative to commodity plastics (Vert M., J. Macromol. Sci. Pure Appl. Chem. A. (1995). 32: 787-97 and Mayer J M, Kaplan D L, Trends Polym. Sci. (1994). 2: 227-8). Poly(butylene succinate), poly(butylene succinate-adipate) copolymer, and poly(ethylene succinate) have successfully been prepared through condensation reactions of glycols with aliphatic dicarboxylic acids6 and commercialized under the trade mark of BIONOLLE™. Aliphatic polyesters have been proven to undergo enzymatic hydrolysis by cholesterol esterase, Rizopus delemaer lipase and by non-enzymatic hydrolysis (Shirahama H, et al, J. Appl. Polym. Sci. (2001). 80: 340-347).
Among aliphatic di-acids, succinic acid is one of the most attractive building blocks for constructing biocompatible biodegradable polymers since it is a naturally occurring product widely used in the food industry and in perfumery. Derivatives of succinic acid undergo strong intramolecular catalysis due to the 1,2 (vicinal) positions of the acting groups. For example, it is well known (Vigneron B, et al. Bull. Soc. Chim. Belg., (1960). 69: 616 and Cohen T, and Lipowitz J, J. Am. Chem. Soc., (1964). 86: 5611) that vicinal amide bonds catalyze the hydrolysis of amide or ester linkages, such as is the case for succinic acid di-amide and ester amide (scheme below).

Despite this progress in knowledge of the art, the need exists for new and better polyamides and poly(ester amides), such as those composed of succinic acid as potentially self-degradable polymers.
The synthesis of high-molecular-weight poly(succinic amides) using traditional polycondensation (PC) methods—High Temperature PC (HTPC) in melt or high-boiling organic solvents, and Low Temperature PC (LTPC) in solution or interfacially—is problematic due to extensive chain termination connected with the formation of five-member succinimide cyclization.

For this reason, high-molecular-weight film-forming polyamides (PAs) were not described in the literature until 1986. Then Katsarava et al. (Makromol. Chem., B. (1986). 187: 2053) published an account of the first synthesis of high-molecular-weight poly(succinamides) obtained by interaction of active succinates with diamines (free bases) under mild conditions using solution active polycondensation (APC).

Application of this approach to the synthesis of amino acid-based poly(ester amides) using di-p-toluene sulfonic acid salts instead of free diamines, however, yielded low molecular weight poly(ester amides) that form brittle films. This result could be attributed to the necessity of using relatively harsh reaction conditions (e.g., 80° C.), which are favorable for cyclization and may cause some imide formation, although to a lesser extent than in HTPC and LTPC. However, extent of cyclization was high enough to result in chain termination, which resulted in decreased molecular weights of the PEAs. This result was attributed to the fact that, after interaction of one ester group in the active succinate, the additional ester groups present, which are as active as the first one, can participate in a cycle-forming (chain termination) reaction in parallel with an aminolysis (chain growth) reaction.
In the early eighties, Tsamantakis et al. (Angew. Makrom. Chem. (1982) 104: 19-30) described diester-di-acid type new monomers and their active di-(p-nitrophenyl) esters. In these studies, alkylene-dicarboxylate monomer syntheses involved succinic or glutaric acids and α,ω-diols. Bis-succinates or bis-glutarates of diols successfully polycondensed with aliphatic or aromatic diamines to yield polymers with moderate to high (up to 1.76 dL/g) inherent viscosities. However, the resulting degradable polymers contained toxic diamines, limiting their potential for biomedical application.
Therefore, the need exists for new and better methods for synthesis of alkylene-dicarboxylate-containing biocompatible and biodegradable poly(ester-amides) (PEAs), compositions containing such PEAs, and methods of their use. The need also exists for new alkylene dicarboxylates for use in making such PEA compositions.